Among various endpoints currently used in the setting of HlV-1 infection, CD4 cell count represents the most extensively studied surrogate marker and might be predictive of the clinical effects of antiretroviral therapy. In some situations, it is highly correlated with clinical outcome at various points of time of antiretroviral therapy. However, it does not always correlate with clinical events, suggesting that the benefits of antiretroviral therapy may be due, at least in part, to factors not reflected in the effect of antiretroviral therapy on CD4 cell counts. In this regard, there are data suggesting that viral load represents a major determinant of the severity of HlV-1 related diseases and is associated with the stage and progression of immunological deterioration. HIV-1 particle numbers determined by using the polymerase chain reaction have been reported to reflect viremia status and viral load in individuals with HIV-1 infection and may serve as a potential clinical marker to monitor the disease process and effectiveness of antiretroviral therapy. It has recently been shown that therapy with simultaneous administration of zidovudine and didanosine provides more sustained elevation in CD4 cells than alternating therapy with the two agents over a time period of one year, suggesting that the dosing schedule of anti-HIV-1 drugs can be an important variable. In this study, we examined the changes in viremia levels and the development of drug-related mutations in 26 patients with symptomatic HIV-1 infection participating on a randomized trial comparing an alternating or simultaneous regimen of AZT and ddI therapy. Patients on both arms had significant reduction in serum RNA copies from baseline throughout the two years of the study. Significant differences between the two arms were demonstrated over the first 2-3 months of therapy. Analyses employing the nested PCR method revealed that the emergence of the ddI- related Leu74/EVal mutation was significantly blocked in both regimens while that of the AZT-related mutation at codon 215 was not affected. Determination of the overall durability of the anti-viremic effect of the alternating and simultaneous regimens of AZT and ddl and clinical implications of the results require further research.